Somatic mutation of the von Hippel-Lindau (VHL) tumor suppressor gene is associated with sporadic renal cell carcinoma (RCC), and germline VHL mutation results in VHL disease with predisposition to RCC and/or other neoplasms. Despite striking genotype-phenotype correlations in VHL disease, disruption of specific pVHL functions is not directly related to the spectrum of clinical disease. I will examine representative RCC- predisposing VHL mutations in vitro and in vivo to identify mutant pVHL functions important for renal tumorigenesis. I hypothesize that VHL mutations exert their tissue-specific effects by disrupting wild-type or introducing novel pVHL functions and that other genetic events are necessary to cause invasive kidney cancer. I will delineate the key genetic events using chemical and insertional mutagenesis. Potassium bromate, a byproduct of water distillation, causes oxidative damage, mutations, and RCC in the renal tubules of rats. I will use this biologically-relevant, kidney-targeted environmental toxin to perform chemical mutagenesis in wild-type and VHL-mutant mice. I will supplement this approach with insertional mutagenesis using a mammalian transposition system targeted to the renal parenchyma.